Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis

• Published in: mBio 2023-04, Vol.14 (2), p.e0015923-e0015923
• Main Authors: Chakraborty, Arijit, Kabashi, Asel, Wilk, Samuel, Rahme, Laurence G
• Format: Article
• Language: English
• Subjects: 2-aminoacetophenone; Autophagy; Beclin-1 - metabolism; Epigenesis, Genetic; Fatty Acids, Monounsaturated - metabolism; Histone Deacetylase 1 - metabolism; Host-Microbial Interactions; immunometabolism; macrophages; Macrophages - metabolism; persistence; Pseudomonas aeruginosa; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - metabolism; quorum sensing; Research Article
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.00159-23

Macrophages are crucial components of the host's defense against pathogens. Recent studies indicate that macrophage functions are influenced by lipid metabolism. However, knowledge of how bacterial pathogens exploit macrophage lipid metabolism for their benefit remains rudimentary. We have shown that the Pseudomonas aeruginosa MvfR-regulated quorum-sensing (QS) signaling molecule 2-aminoacetophenone (2-AA) mediates epigenetic and metabolic changes associated with this pathogen's persistence . We provide evidence that 2-AA counteracts the ability of macrophages to clear the intracellular P. aeruginosa, leading to persistence. The intracellular action of 2-AA in macrophages is linked to reduced autophagic functions and the impaired expression of a central lipogenic gene, stearoyl-CoA desaturase 1 ( ), which catalyzes the biosynthesis of monounsaturated fatty acids. 2-AA also reduces the expression of the autophagic genes Unc-51-like autophagy activating kinase 1 ( ) and and the levels of the autophagosomal membrane protein microtubule-associated protein 1, light chain 3 isoform B (LC3B) and p62. Reduced autophagy is accompanied by the reduced expression of the lipogenic gene , preventing bacterial clearance. Adding the SCD1 substrates palmitoyl-CoA and stearoyl-CoA increases P. aeruginosa clearance by macrophages. The impact of 2-AA on lipogenic gene expression and autophagic machinery is histone deacetylase 1 (HDAC1) mediated, implicating the HDAC1 epigenetic marks at the promoter sites of and genes. This work provides novel insights into the complex metabolic alterations and epigenetic regulation promoted by QS and uncovers additional 2-AA actions supporting P. aeruginosa sustainment in macrophages. These findings may aid in designing host-directed therapeutics and protective interventions against P. aeruginosa persistence. This work sheds new light on how P. aeruginosa limits bacterial clearance in macrophages through 2-aminoacetophenone (2-AA), a secreted signaling molecule by this pathogen that is regulated by the quorum-sensing transcription factor MvfR. The action of 2-AA on the lipid biosynthesis gene and the autophagic genes and appears to secure the reduced intracellular clearance of P. aeruginosa by macrophages. In support of the 2-AA effect on lipid biosynthesis, the ability of macrophages to reduce the intracellular P. aeruginosa burden is reinstated following the supplementation of palmitoyl-CoA and stearoyl-CoA. The 2-AA-mediated reduction of